FATE AND TOXICITY OF 2-(FLUOROMETHOXY)-1,1,3,3,3-PENTAFLUORO-1-PROPENE (COMPOUND A)-DERIVED MERCAPTURATES IN MALE, FISCHER-344 RATS

Background: 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1 pene (compound A ) is formed In the anesthesia circuit by the degradation of sevofluran e. Compound A is nephrotoxic in rats and undergoes metabolism by the m ercapturic acid pathway in rats and humans to yield the mercapturates )-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L-cysteine (compound 3) and ,3 ,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cysteine (compound 5). These e xperiments were designed to examine the fate and nephrotoxicity of com pound A-derived mercapturates in rats. Methods: The deacetylation of c ompounds 5 and 5 by human and rat kidney cytosol and with purified acy lases I and hi was measured, and. their nephrotoxicity was studied in male Fischer 344 rats. The metabolism of the deuterated analogs of com pounds 3 and 5, )-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L-cysteine (co mpound-3-d(3)) and ,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cysteine (compound 5-d(3)), respectively, was measured. Results: Compound 5, bu t not compound 3, was hydrolyzed by human and rat kidney cytosols and by acylases I and III. P-19 nuclear magnetic resonance spectroscopic a nalysis showed no urinary metabolites of compound 3, but unchanged com pound 5 and its metabolites 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and fluoroethyl]-4,5-dihydro-1,3-thiazole-4-carboxylic acid were detected in urine. Compound 5 (250 mu M/kg) produced clinical chemica l and morphologic evidence of renal injury in two of three animals stu died. Conclusions: Compounds 3 and 5 underwent little metabolism. Comp ound 5, but not compound 3, was mildly nephrotoxic, These results indi cate that compound A-derived mercapturate formation constitutes a deto xication pathway for compound A.